Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support

Flood, Dillon T.; Asai, Shota; Zhang, Xintong; Wang, Jie; Yoon, Leonard; Adams, Zoë C.; Dillingham, Blythe C.; Sanchez, B; Vantourout, Julien C.; Flanagan, Mark E.; Piotrowski, David W.; Richardson, Paul G.; Green, Samantha; Shenvi, Ryan A.; Chen, Jason; Baran, Phil S.; Dawson, Philip

doi:10.26434/chemrxiv.7966706.v1

Cited by 13 publications

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“…RASS is a process that allows for the adsorption of biomacromolecules onto a solid support to facilitate their transfer into solvents or reaction paradigms that would previously be considered incompatible. 37 − 40 In this manifestation, DNA is adsorbed onto a polystyrene-based cationic support, through a simple mixing procedure, and the solvent exchanged (by simple washing and drying) into near-anhydrous conditions. In turn, water-incompatible reactions are enabled.…”

Section: Chemical Approach To Site-specific Dna Modificationmentioning

confidence: 99%

“…This is important as there exists evidence that DNA retains its secondary structure while adsorbed to the support. 37 High Tm DNA hairpins with nonoverhanging terminal alcohols were labeled in higher conversions when thermally denatured while being adsorbed to the support (see Supporting Information ). With all of these elements combined, the development of SENDR was complete, and our attention turned to its application.…”

Section: Chemical Approach To Site-specific Dna Modificationmentioning

confidence: 99%

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Synthetic Elaboration of Native DNA by RASS (SENDR)

et al. 2020

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Controlled site-specific bioconjugation through chemical methods to native DNA remains an unanswered challenge. Herein, we report a simple solution to achieve this conjugation through the tactical combination of two recently developed technologies: one for the manipulation of DNA in organic media and another for the chemoselective labeling of alcohols. Reversible adsorption of solid support (RASS) is employed to immobilize DNA and facilitate its transfer into dry acetonitrile. Subsequent reaction with P(V)-based Ψ reagents takes place in high yield with exquisite selectivity for the exposed 3′ or 5′ alcohols on DNA. This two-stage process, dubbed SENDR for Synthetic Elaboration of Native DNA by RASS, can be applied to a multitude of DNA conformations and sequences with a variety of functionalized Ψ reagents to generate useful constructs.

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Section: Chemical Approach To Site-specific Dna Modificationmentioning

confidence: 99%

Section: Chemical Approach To Site-specific Dna Modificationmentioning

confidence: 99%

Synthetic Elaboration of Native DNA by RASS (SENDR)

et al. 2020

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“…For example, an impressive application comes from Baran and Dawson, wherein they demonstrated Ni-catalyzed electrochemical amination of DNA in organic solvents using a reversible adsorption to solid support approach (RASS). 120 This work enhanced the scope of chemistries available to DNA encoded library (DEL) research. The MacMillan group developed a highly selective cellular microenvironment protein mapping protocol that employs photocatalytic carbene generation via Dexter energy transfer from an iridium photocatalyst to diazirines.…”

Section: Discussionmentioning

confidence: 96%

New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry

et al. 2020

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As the breadth of radical chemistry grows, new means to promote and regulate single-electron redox activities play increasingly important roles in driving modern synthetic innovation. In this regard, photochemistry and electrochemistry—both considered as niche fields for decades—have seen an explosive renewal of interest in recent years and gradually have become a cornerstone of organic chemistry. In this Outlook article, we examine the current state-of-the-art in the areas of electrochemistry and photochemistry, as well as the nascent area of electrophotochemistry. These techniques employ external stimuli to activate organic molecules and imbue privileged control of reaction progress and selectivity that is challenging to traditional chemical methods. Thus, they provide alternative entries to known and new reactive intermediates and enable distinct synthetic strategies that were previously unimaginable. Of the many hallmarks, electro- and photochemistry are often classified as “green” technologies, promoting organic reactions under mild conditions without the necessity for potent and wasteful oxidants and reductants. This Outlook reviews the most recent growth of these fields with special emphasis on conceptual advances that have given rise to enhanced accessibility to the tools of the modern chemical trade.

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“…26,31 Approaches to improve the tolerance of the DNA barcode to high levels of organic solvent using cationic resins are currently being explored. 32 Though these methods can expand the scope of DNA-compatible chemistry dramatically, they present their own set of challenges when applied to library syntheses.…”

Section: Introductionmentioning

confidence: 99%

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

Gerry

Wawer²,

Clemons³

et al. 2019

Preprint

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It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multi-fusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have “drug-like” properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (e.g., commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC50 = 20.1–68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.

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Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support

Cited by 13 publications

References 0 publications

Synthetic Elaboration of Native DNA by RASS (SENDR)

Synthetic Elaboration of Native DNA by RASS (SENDR)

New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

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